Diagnostic Magnetic Resonance Imaging of Atherosclerosis in Apolipoprotein E Knockout Mouse Model Using Macrophage-Targeted Gadolinium-Containing Synthetic Lipopeptide Nanoparticles
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Published on: May 2, 2022
Zu T Shen1, Shaokuan Zheng2, Matthew J Gounis2
1SignaBlok, Inc, Shrewsbury, Massachusetts, United States of America.
Insights
We developed optimized gadolinium-based contrast agents (GBCA-HDL) that target macrophages to improve atherosclerotic plaque detection via MRI. Spherical particles enhance imaging and reduce kidney exposure to gadolinium.
Area of Science:
- Biomedical imaging
- Cardiovascular research
- Nanotechnology
Background:
- Cardiovascular disease is a leading cause of death, often due to vulnerable atherosclerotic plaque rupture.
- Macrophages within plaques are key indicators of vulnerability, but current MRI lacks plaque content characterization.
- Previous work demonstrated macrophage-targeted gadolinium (Gd)-based contrast agent (GBCA-HDL) particle efficacy in plaque detection.
Purpose of the Study:
- To optimize GBCA-HDL particle shape and composition for enhanced atherosclerotic plaque MRI detection.
- To investigate the effect of particle characteristics on in vivo macrophage targeting and uptake.
- To assess the organ clearance profiles of different GBCA-HDL particle shapes.
Main Methods:
- In vitro and in vivo studies using J774 macrophages and apolipoprotein (apo) E knockout (KO) mouse models.
- Evaluation of macrophage-targeted GBCA-HDL particles with varying shapes and compositions.
- Magnetic resonance imaging (MRI) to assess plaque-to-muscle normalized enhancement ratio (NER).
- Analysis of particle uptake by intraplaque macrophages and organ clearance.
Main Results:
- Optimized GBCA-HDL particles demonstrated efficient intracellular delivery and uptake by macrophages, both in vitro and in vivo.
- Achieved enhanced plaque detection with NER up to 160% and higher, indicating high diagnostic potential.
- Spherical GBCA-HDL particles exhibited hepatic clearance, contrasting with discoidal particles, potentially reducing renal gadolinium burden.
- Activated macrophages, targeted by GBCA-HDL, are implicated in various inflammatory conditions beyond atherosclerosis.
Conclusions:
- Optimized GBCA-HDL particles significantly improve MRI detection of vulnerable atherosclerotic plaques.
- Spherical particle design offers potential for reduced renal adverse effects associated with gadolinium.
- This macrophage-targeting approach holds promise for diagnosing and monitoring inflammatory diseases beyond cardiovascular conditions.
Abstract:
Cardiovascular disease is the leading cause of death in Western cultures. The vast majority of cardiovascular events, including stroke and myocardial infarction, result from the rupture of vulnerable atherosclerotic plaques, which are characterized by high and active macrophage content. Current imaging modalities including magnetic resonance imaging (MRI) aim to characterize anatomic and structural features of plaques rather than their content. Previously, we reported that macrophage-targeted delivery of gadolinium (Gd)-based contrast agent (GBCA-HDL) using high density lipoproteins (HDL)-like particles significantly enhances the detection of plaques in an apolipoprotein (apo) E knockout (KO) mouse model, with an atherosclerotic wall/muscle normalized enhancement ratio (NER) of 120% achieved. These particles are comprised of lipids and synthetic peptide fragments of the major protein of HDL, apo A-I, that contain a naturally occurring modification which targets the particles to macrophages. Targeted delivery minimizes the Gd dose and thus reduces the adverse effects of Gd. The aims of the current study were to test whether varying the GBCA-HDL particle shape and composition can further enhance atherosclerotic plaque MRI and control organ clearance of these agents. We show that the optimized GBCA-HDL particles are efficiently delivered intracellularly to and uptaken by both J774 macrophages in vitro and more importantly, by intraplaque macrophages in vivo, as evidenced by NER up to 160% and higher. This suggests high diagnostic power of our GBCA-HDL particles in the detection of vulnerable atherosclerotic plaques. Further, in contrast to discoidal, spherical GBCA-HDL exhibit hepatic clearance, which could further diminish adverse renal effects of Gd. Finally, activated macrophages are reliable indicators of any inflamed tissues and are implicated in other areas of unmet clinical need such as rheumatoid arthritis, sepsis and cancer, suggesting the expanded diagnostic and prognostic use of this method.
